Oncogenic cancer/testis antigens are a hallmarker of cancer and a sensible target for cancer immunotherapy.

Increasing evidence shows that numerous cancer-testis antigens (CTAs) are uniquely overexpressed in various types of cancer and most CTAs are oncogenic. Overexpression of oncogenic CTAs promotes carcinogenesis, cancer metastasis, and drug resistance. Oncogenic CTAs are generally associated with poor prognosis in cancer patients and are an important hallmark of cancer, making them a crucial target for cancer immunotherapy. CTAs-targeted antibodies, vaccines, and chimeric antigen receptor-modified T cells (CAR-T) have recently been used in cancer treatment and achieved promising outcomes in the preclinical and early clinical trials. However, the efficacy of current CTA-targeted therapeutics is either moderate or low in cancer therapy. CTA-targeted cancer immunotherapy is facing enormous challenges. Several critical scientific problems need to be resolved: (1) the antigen presentation function of MHC-I protein is usually deficient in cancer patients, so that very low amounts of intracellular CTA epitopes are presented to tumor cell membrane surface, leading to weak immune response and subsequent immunity to CTAs; (2) various immunosuppressive cells are rich in tumor tissues leading to diminished tumor immunity; (3) the tumor tissue microenvironment markedly reduces the efficacy of cancer immunotherapy. In the current review paper, the authors propose new strategies and approaches to overcome the barriers of CTAs-targeted immunotherapy and to develop novel potent immune therapeutics against cancer. Finally, we highlight that the oncogenic CTAs have high tumor specificity and immunogenicity, and are sensible targets for cancer immunotherapy. We predict that CTAs-targeted immunotherapy will bring about breakthroughs in cancer therapy in the near future.